Computational drug absorption

Palm, K., Luthman, K., Ungell, A.-L., Strandlund, G., Beigi, F., Lundahl, P., Artursson, P. Evaluation of dynamic polar molecular surface area as predictor of drug absorption comparison with other computational and experimental predictors. J. Med. Chem. 1998, 41, 5382-5392. 

Stenberg, P., Norinder, U., Luthman, K., Artursson, P. Experimental and computational screening models for the prediction of intestinal drug absorption. 

Application of ultra-high-throughput in silico estimation of biopharmaceutical properties to the generation of rule-based computational alerts has the potential to improve compound selection to those drug candidates that are likely to prove less troublesome in their development. The extension of purely in silico methods to the realm of mechanistic simulation further enhances our ability to predict the impact of physiological and biochemical process on drug absorption and bioavailability. 

This volume gives an overview of the current status and an outlook to future more reliable predictive approaches. It is subdivided in five sections dealing with studies of membrane permeability and oral absorption, drug dissolution and solubility, the role of transporters and metabolism in oral absorption, computational approaches to drug absorption and bioavailability, and finally with certain drug development issues. 

Theory and computational aspects of intestinal permeability have been reviewed in detail by Egan and Lauri [27], Briefly, a drug must be somewhat permeable through the membrane of the intestinal tract if it is to be administered orally and achieve systemic exposure. The rate of membrane permeability is strongly related to the lipophilicity and hydrophilicity of the molecule. Thus, models with a small number of descriptors related to those two properties can provide useful predictions of drug absorption. 

The development of combinatorial chemistry and high throughput screening programmes has stimulated efforts to find experimental and computational models to estimate and predict drug absorption, distribution, metabolism and elimination based on drug physicochemical properties. 

Neumann D, Kohlbacher O, Merkwirth C, Lengauer T (2006) A fully computational model for predicting percutaneous drug absorption. J Chem Inf Model 46 424-429. 

It is absolutely impossible, no matter what any well-meaning but misguided animal protectionist may claim, to simulate the enormously complicated scenario that occurs in an animal body with any in vitro system, combination of in vitro systems, or computer programs, since we know only a fraction of what actually happens in drug absorption and delivery to target tissue. Table 16.1 presents an overview of this complexity. 

Verma, R.P., Hansch, C. and Selassie, C.D. (2007) Comparative QSAR studies on PAMPA/modified PAMPA for high throughput profiling of drug absorption potential with respect to Caco-2 cells and human intestinal absorption. Journal of Computer-Aided Molecular Design, 21, 3-22. 

Hou, T., Wang, J Zhang, W Wang, W. and Xu, X. (2006) Recent advances in computational prediction of drug absorption and permeability in drug discovery. Current Medicinal Chemistry, 13, 2653-2667. 

Lipinski et al. (1997) published a review article on computational and experimental methods of estimating aqueous solubility, serving as a useful reference of available methods. The article discusses poor solubility as a potential limiting factor to overall drug absorption across the gut wall. 

Although various computational approaches for the prediction of intestinal drug permeability and solubility have been reported [219], recent computer-based absorption models utilize a large number of topological, electronic, and geometric descriptors in an effort to take both aqueous drug solubility and permeability into account. Thus, descriptors of partitioned total surface areas [168], Abraham molecular descriptors [220,221], and a variety of structural descriptors in combination with neural networks [222] have been shown to be determinants of oral drug absorption. 

Palm. K., Artursson. P. and Luthmann, K. Experimental and Theoretical Predictions of Intestinal Drug Absorption. In Computer-Assisted Lead Finding and Optimization Current Tools for Medicinal Chemistry, Eds van de Waterbeemd, H., Testa, B. and Folkers, G., Wiley-VCH, Weinheim, 1997, pp. 277-289. 

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